tbuckley/cabot-search huggingface dataset:
Abstract 854: The role of protocadherin, FAT2 in breast cancer
Authors: Thomas Roache, Megan Sumera, Zalaila Laird, Amrita Datta
Journal: Cancer Research (2022)

Abstract Protocadherins are cell adhesion molecules that belong to the cadherin superfamily. They are novel cadherin like proteins predominantly associated with early development and morphogenesis, cell growth and patterning, cell-cell adhesion, cell motility (including cell invasion and migration). The Fat-protocadherins are derived from an ancestral Drosophila FAT like cadherin and are evolutionarily conserved. They have been primarily implicated in neuronal cell development and cancer. Several studies have implicated protocadherin dysfunction in cancer. Loss of protocadherin expression, chromosome deletion and epigenetic silencing have been implicated in kidney, prostate, colorectal and breast cancer. More recently they have been implicated in gastric tumors and gliomas. Based on these findings, protocadherins are thought to be tumor suppressors and in general seem to regulate cancer cell proliferation, migration and/or apoptosis. However, multiple exceptions have also been observed and individual protocadherin functions seem to be context-dependent, as some can be considered either tumor suppressors or proto-oncogenes according to the type of cancer being examined. The mechanistics of the roles of the protocadherins in neuronal development have been well dissected but most oncological studies have focused on their characterization as potential biomarkers while the molecular signaling pathways through which the protocadherins regulate growth, invasion and metastasis are still poorly understood. For example recent research has shown that FAT1 is repressed in oral cancer owing to homozygous deletion or epigenetic silencing and is preferentially downregulated in invasive breast cancer. On the other hand, FAT1 is upregulated in leukemia and prognosis of preB-ALL patients with FAT1 upregulation is poor. Therefore FAT1 is tumor suppressive or oncogenic in a context-dependent manner, while FAT4 is tumor suppressive. FAT2 is highly expressed in breast cancer and lung squamous cell carcinoma and the elevated expression of FAT2 is correlated with poor patient outcome.Our preliminary research analysis of the TCGA data from the Genomic Data Commons Portal shows that protocadherins FAT4 and FAT1 are among the top dysregulated genes in cancer. We have also determined that FAT2 has higher Copy Number Variation (CNV) gain events than loss events. Given that there is a well-known concordance between CNV and differential gene expression we believe that FAT2 has a paradoxical oncogenic role in breast cancer. Citation Format: Thomas Roache, Megan Sumera, Zalaila Laird, Amrita Datta. The role of protocadherin, FAT2 in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 854.
Abstract 167: Pre-clinical characterization of a novel series of FGFR2 selective inhibitors with potency against clinically relevant mutations
Authors: John Fischer, Karyn Bouhana, Mark J. Chicarelli, Josh Dahlke, Brad Fell, Jennifer Fulton, Anna Guarnieri, Ravi Jalluri, Amber Johnson, Brent Mclean, Max Mejia, Rob Rieger, John Robinson, Mareli Rodriguez, Francis Sullivan, Yang Wang, Shannon Winski, Yeyun Zhou
Journal: Cancer Research (2022)

Abstract The fibroblast growth factor receptor (FGFR) family of protein tyrosine kinases plays a role in many physiological processes including angiogenesis and wound healing. FGFR mutations, fusions, rearrangements, and amplifications have been linked to the pathogenesis of multiple tumor types. For example, approximately 10-15% of patients with intrahepatic cholangiocarcinoma have FGFR2 fusions, and amplification of FGFR2 is prevalent in gastric cancer and implicated in tumor growth. Approved FGFR inhibitors produce responses in patients that harbor FGFR genetic alterations but show reduced activity against key mutations (e.g., V565, N550, etc.). These pan-FGFR inhibitors also frequently show dose-limiting toxicities including hyperphosphatemia which can be linked to the inhibition of FGFR1. To address these issues, a novel series of FGFR inhibitors that are potent and selective reversible inhibitors of FGFR2 with selectivity over FGFR1 have been identified. This series also maintains activity against clinically relevant mutations in the FGFR2 protein. Inhibition of cellular FGFR phosphorylation was measured using engineered cell lines to demonstrate that the inhibitors target both wild-type FGFR2 and activating FGFR2 mutations while sparing FGFR1. In addition, CDX tumor models showed in vivo target engagement and FGFR isoform selectivity. Herein, the in vitro and in vivo characterization of a representative selective reversible FGFR2 inhibitor is described. Citation Format: John Fischer, Karyn Bouhana, Mark J. Chicarelli, Josh Dahlke, Brad Fell, Jennifer Fulton, Anna Guarnieri, Ravi Jalluri, Amber Johnson, Brent Mclean, Max Mejia, Rob Rieger, John Robinson, Mareli Rodriguez, Francis Sullivan, Yang Wang, Shannon Winski, Yeyun Zhou. Pre-clinical characterization of a novel series of FGFR2 selective inhibitors with potency against clinically relevant mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 167.
Abstract 3694: The role of the p40 family in pancreatic cancer
Authors: Monica Sheinin
Journal: Cancer Research (2022)

Abstract Pancreatic cancer is the fourth leading cause of cancer in the US, and mortality is rising rapidly with little improvement in survival rates. Treatment remains a major challenge of this disease and these poor outcomes have researchers targeting the tumor microenvironment for therapy. The diagnosis and therapeutic options remain an obstacle due to the immune system response and associated non- specific symptoms. Immunotherapy is an important treatment for pancreatic cancer, and its applications are currently being studied. Targeting T cells to recognize and kill tumor cells could be a potential strategy. Due to the behavior of pancreatic cancer and the tumor microenvironment, immunosuppressive cells such as myeloid - derived suppressor cells and regulatory T cells limit the efficacy of T cell infiltration. The cytokine interleukin-12 (IL-12) plays an essential role to regulate both innate (natural killer cells) and adaptive (cytokine T-lymphocytes) immunities in cancer therapies. IL-12 is composed of two subunits, p40 and p35. We found that various human pancreatic cancer cells produce greater levels of p40 monomer and p40 homodimer (p402), than IL-12, and IL-23. We further demonstrate that selective neutralization of p40 by p40 mAb (a3-3a), by p402 mAb (d7-12c) stimulated death in pancreatic cancer cells. Our studies aim to identify the roles of p40 and p402 in pancreatic cancer cells and underlie the importance of p40 monomer and p40 homodimer in helping cancer cells escape cell death. Citation Format: Monica Sheinin. The role of the p40 family in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3694.
Abstract 5253: SMO as a predicted biomarker on immunotherapy and correlated with immune infiltrates in mCRC
Authors: Jinlin Cai, Dandan Fan, Yaoxu Chen, Mengli Huang
Journal: Cancer Research (2022)

Abstract Background: Colorectal cancer has become a common gastrointestinal tumor. Immune checkpoint inhibitors (ICIs) including pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. SMO, a gene encodes Smoothened protein, which is an important signal converter in Sonic Hedgehog (SHH) signal pathway. Studies have shown that CTLA-4 expressing CD3+ lymphocytes were observed in atypical and malignant meningioma and tumors harboring SMO mutation, suggested that SMO may be related to immune microenvironment and tumor immunity, but the association between SMO mutation and TMB or survival in metastatic Colorectal Cancer(mCRC) is unknown. Methods: Genomic and survival data of mCRC patients administrated with ICIs were retrieved from publicly accessible data (Pancancer.Samstein2018.NGS.1661) and the association between SMO mutation overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank tests. The association between SMO mutation and TMB was also analyzed in this public immunotherapy-treated cohort, Wilcoxon test was used for the comparison of TMB. In addition, Genomic, immune cell infiltration data of 149 patients with Rectum Adenocarcinoma (READ) was obtained from The Cancer Genome Atlas (TCGA). The correlation analysis between immune cell infiltration and SMO mutation status was further analyzed by CIBERSORT. Statistical significance was set at p=0.05. Results: 7.3% (8/109) patients in the clinical cohort harbored SMO mutation. Survival analysis in the public cohort demonstrated that SMO mutation resulted in significantly longer OS (10.5 vs 8 months; HR, 0; p=0.035) in mCRC patients treated with ICIs. Moreover, SMO mutation is associated with higher TMB in public cohort (p&amp;lt;0.0001). Furthermore, the correlation analysis between immune infiltration and SMO mutation status in mCRC which was analysed in TCGA shows that M1 macrophages, CD8 T cells, Gamma Delta T cells increased significantly (p=0.048, p=0.043, p=0.002). Conclusions: This study shows that SMO mutation may serve as a potential positive biomarker of ICIs in melanoma since it relatively correlated with higher TMB. In addition, the up regulation of M1 macrophages, CD8 T cells, as well as the Gamma Delta T cells may be another potential mechanism for the better efficacy of ICIs in patients with SMO mutation. Citation Format: Jinlin Cai, Dandan Fan, Yaoxu Chen, Mengli Huang. SMO as a predicted biomarker on immunotherapy and correlated with immune infiltrates in mCRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5253.
Abstract 4059: Design and in vitro antitumor analysis of a novel diphenyltin complex (diphenyltin dioxalate)
Authors: Jade Witter, Xuequing Song, Alexandra Taraboletti, William Li, Tajera Henry
Journal: Cancer Research (2022)

Abstract Organotins are popular among chemists due to their potential biological properties against bacteria, fungus, and cancer cell lines. In particular, organotins have been utilized in chemotherapeutic applications. Compared to cisplatin, organotins give more favorable toxicological profiles and better cytotoxicity and antiproliferative activities. However, organotins have limited biological applications due to their poor water solubility. In this study we synthesized a diphenyltin complex (Diphenyltin Dioxalate) that possesses partial ionic characteristics, by reacting a diprotic carboxylic acid, with triphenyltin chloride in the presence of di-isopropylamine. A tin-carbon cleavage reaction was observed, as IR/NMR spectroscopy and X-ray Crystallography studies showed that diphenyltin dioxalate was successfully obtained in the reaction. Post synthesis solubility tests were performed to examine diphenyltin dioxalate’s water-soluble nature, compared to its precursor triphenyltin. Diphenyltin dioxalate was then tested to examine its cytotoxicity and antitumor activity on human glioblastoma cell model (T98G) and a normal human oligodendrocyte cell model (MO3.13). Further studies with the complex will consist of synthetic mechanistic studies on the Sn-C cleavage. Citation Format: Jade Witter, Xuequing Song, Alexandra Taraboletti, William Li, Tajera Henry. Design and in vitro antitumor analysis of a novel diphenyltin complex (diphenyltin dioxalate) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4059.
Gold@Halloysite nanotubes-chitin composite hydrogel with antibacterial and hemostatic activity for wound healing
Authors: Puxiang Zhao, Yue Feng, Youquan Zhou, Cuiying Tan, Mingxian Liu
Journal: Bioactive Materials (2022)

Infection and healing of wounds after injury has always been an unavoidable problem in daily life, so design of a biomaterial with antibacterial and good wound healing properties is highly needed. Herein, a wound healing hydrogel dressing with halloysite clay and chitin as the main components was prepared, which combines the advantages of the biomacromolecule and clay. Halloysite nanotubes (HNTs) are extremely biocompatible clay materials with a hollow tubular structure, and the inner and outer surfaces of HNTs are composed of SiOx and AlOx layers with different charges. Au nanoparticles with diameter in 5-10 nm were filled into the HNTs' lumen to endow photothermal effect of the clay materials. Au@HNTs was then mixed with chitin solution to prepare flexible composite hydrogel by crosslinking by epichlorohydrin. The antibacterial properties, biocompatibility and hemostatic properties of the hydrogel material were investigated by antibacterial experiments, cell experiments, mouse liver and tail hemostatic experiments. After infecting the back wound of mice with Staphylococcus aureus, the hydrogel was applied to the wound to further verify the killing effect on bacteria and wound healing effect of the hydrogel material in vivo. The Au@HNTs-chitin composite hydrogel exhibits high antibacterial and hemostatic activity as well as promoting wound healing function with low cytotoxicity. This study is significant for the development of high-performance wound dressings based on two commonly used biocompatible materials, which shows promising application in wound sterilization and healing.
Abstract 6105: Single high-dose irradiation induced iRhom2 up-regulation promotes macrophage anti-tumor activity through cGAS/STING signaling
Authors: Xiaomei Zhao, Shisuo Du, Biao Wang, Zhaochong Zeng
Journal: Cancer Research (2022)

Abstract Clinical application of Stereotactic body radiotherapy (SBRT) allows high dose of radiation to be delivered to extracranial target within the body safely, however, high dose per fraction and with fewer fractions(hypofractionation) opened up the radiation oncology field to new questions on variety of dose-fractionation schedules, especially, the immunomodulatory effects of radiotherapy, which changes following the variety of dose-fractionation schedules. In the present study, we excluded the direct antitumor effect of radiation by comparing three different fractionation schedules –8*2Gy, 3*4.5Gy, 1*10Gy, which have the same biologically effective dose (BED). We found the fractionation schedules 1*10Gy had a significant higher antitumor effect, suggesting that a single high-dose induced a more enhanced anti-tumor immunity compared to the conventionally fractionation(8*2Gy) and moderately fractionation (3*4.5Gy). However, in STING deficiency mice, we failed to find a different tumor control effect among the three dose-fractionation schedules, suggesting cGAS/STING signaling was involved in regulating immunomodulatory effects that leading to different anti-tumor immunity. Further mechanism investigation revealed that single high-dose irradiation induced up-regulation of iRhom2 in infiltrated macrophage, and iRhom2 promoted cGAS/STING signaling via maintaining stability of STING and facilitating STING trafficking from ER to perinuclear microsomes. Meanwhile, a positive feedback loop between iRhom2 and TNFα sharpened the signaling responses, and amplified antitumor immunity induced by cGAS-STING-IFN pathway after single high-dose irradiation. Taken together, these results suggest that single high-dose irradiation induced iRhom2 up-regulation promotes macrophage anti-tumor activity through cGAS/STING signaling. Citation Format: Xiaomei Zhao, Shisuo Du, Biao Wang, Zhaochong Zeng. Single high-dose irradiation induced iRhom2 up-regulation promotes macrophage anti-tumor activity through cGAS/STING signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6105.
Abstract 2988: Proteasomal deubiquitinases represent an attractive therapeutic target in head and neck squamous cell carcinomas (HNSCC)
Authors: Ethan L. Morgan, Tiffany Toni, Xinping Yang, Hui Cheng, Ramya Viswanathan, Zhong Chen, Carter Van Waes
Journal: Cancer Research (2022)

Abstract Despite recent advances in treatment options for Human Papillomavirus (HPV)- head and neck squamous cell carcinoma (HNSCC), the overall survival (OS) rate for HNSCC is low, demonstrating the need for novel therapies for these cancers. Targeting the ubiquitin-proteasome system (UPS) has emerged as a potential target for the development of novel anti-cancer therapies. Bortezomib, a first generation proteasome inhibitor clinically approved for the treatment of Multiple Myeloma, has previously been demonstrated to induce tumor regression in a subset of HNSCC patients through the inhibition of canonical NFκB activity; however, the failure of Bortezomib to inhibit other pro-survival pathways such as MAPK and STAT3 signalling resulted in heterologous responses. A recently developed alternative to proteasome inhibitors is the small molecule b-AP15, which inhibits the proteasomal deubiquitinases USP14 and UCHL5, thus allowing more specificity and less toxicity than proteasome inhibitors. Here, we show b-AP15 inhibits proliferation and colony formation in multiple HPV- and HPV+ HNSCC cell lines, with minimal effects in normal oral keratinocytes. Furthermore, b-AP15 induces significant caspase-dependent apoptosis. Using siRNA targetting USP14 and UCHL5, only USP14 depletion significantly reduced cell proliferation and colony formation. Mechanistically, b-AP15 treatment reduces TNFα-induced NFκB activity and the expression of pro-survival proteins such as cIAP2 and TRAF2, promoting the formation of the TNFR complex II and sensitizing cells to TNFα-induced cell death. Finally, TCGA data demonstrates that USP14 is highly expressed in HNSCC when compared with normal tissue and is significantly correlated with worse overall survival. Together, we have identified that inhibition of proteasomal deubiquitinases inhibits the proliferation and survival of HNSCC cells and enhanced TNFα-induced cell death via the inhibition of NFκB activity. Our data suggest that combination therapies with b-AP15 could potentially offer a clinical benefit in HNSCC patients by promoting TNFα-induced cytotoxicity. Further studies will focus on the mechanism by which USP14 regulates NFκB signalling in HNSCC cells and the effect of b-AP15 activity in combination with radiation treatment in in vivo mouse xenograft models. Citation Format: Ethan L. Morgan, Tiffany Toni, Xinping Yang, Hui Cheng, Ramya Viswanathan, Zhong Chen, Carter Van Waes. Proteasomal deubiquitinases represent an attractive therapeutic target in head and neck squamous cell carcinomas (HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2988.
Abstract 2419: Understanding the role of DCLK1 mediated invadopodia regulation in HNSCC
Authors: Levi K. Arnold, David Standing, Prabhu Ramamoorthy, Harmony Saunders, Thuc Ly, Shrikant Anant, Sufi Thomas
Journal: Cancer Research (2022)

Abstract Despite therapeutic advances, head and neck squamous cell carcinoma (HNSCC) is marked by high mortality, particularly with increasing stage. Locoregional invasion, an early step in metastasis, is driven by the development of finger-like processes on the tumor cell known as invadopodia. Mature, active invadopodia secrete matrix metalloproteases (MMP) that enable extension of the cell into the extracellular matrix (ECM). Kinesins haul RAB-bound vesicles containing MMPs along microtubules the length of invadopodia for secretion to the most distal aspect of the invadopodia. It is unclear how these kinesins are modulated within invadopodia. In preliminary studies on patient samples, we identified high levels of doublecortin like kinase (DCLK1) at the invasive front of HNSCC. We hypothesize DCLK1 supports the function of kinesins as a mechanism of invasion. DCKL1 was knocked down in HNSCC lines with a short hairpin RNA (shDCLK1). Invasion and migration assays were performed in shDCLK1 and shcontrol tumor cells by utilizing a transwell assay. Confocal microscopy using Leica LAS X, was performed to assess colocalization of DCLK1 and markers of mature invadopodia (cortactin, TKS5, MT1-MMP) in HNSCC lines for. . To validate the association of DCLK1 with Kif16B and RAB40b, we carried out a co-immunoprecipitation analysis. Finally, conditioned media from shDCLK1 and shControl HNSCC cells was used to assess MMP activity using gelatin zymography and MMP profiler arrays. Transwell assay demonstrates reduced movement in shDCLK1 compared to shcontrol tumor cells (p &amp;lt;0.0001 invasion, p &amp;lt;0.001 migration). Confocal microscopy shows colocalization of MMP 9 and DCLK1 to invadopodia. DCLK1 immunoprecipitation show RAB40b and Kif16b complex together. Additionally, DCLK1, RAB40b, and Kif16b colocalize to invadopodia in confocal studies. We found that DCLK1 colocalizes with markers of mature invadopodia, and that DCLK1 colocalizes to Rab40b, Kif16b, and MMP9 within invadopodia. DCLK1 and MMP9 co-localize to invadopodia as well. Cells expressing DCLK1 had increased MMP 1, and 9 (p &amp;lt;0.041, p &amp;lt;0.001) expression compared to shDCLK1 cells. Further, shDCLK1 cells have significantly attenuated MMP 1 and 9 activity as measured by gelatin zymography. These studies reveal a novel role of DCLK1 in the molecular mechanism driving invadopodia, MMP trafficking and signaling. These early studies indicate that targeting DCLK1 in HNSCC may reduce locoregional invasion and help prevent early metastatic spread. Citation Format: Levi K. Arnold, David Standing, Prabhu Ramamoorthy, Harmony Saunders, Thuc Ly, Shrikant Anant, Sufi Thomas. Understanding the role of DCLK1 mediated invadopodia regulation in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2419.